Alcohol dependence is characterized by loss of control over alcohol drinking, tolerance, and physical dependence. Twin, adoption and cross- fostering studies and pedigree analyses indicate that there are inherited as well as environmental determinants for the pathogenesis of this disorder. When the relative contributions of genetic and environmental factors to alcoholism risk were examined genetic factors were found to exert a moderate to strong influence on the development of alcohol dependence for both men (heritability estimate = 0.59) and women (heritability estimate = 0.42). It has been proposed that multiple genes interact with environmental factors in a complex way to either increase or decrease an individual's vulnerability to alcohol dependence. Evidence for genetic influences on the development of alcohol dependence has led to studies of nonalcohol dependent offspring of fathers with the disorder. These high risk children have been compared to their low risk counterparts with no family history of alcoholism. Important biological and psychological differences have been found as a function of a family history of alcoholism. Several lines of evidence suggest that the brain opioid system is part of a neurocircuitry involved in alcohol reinforcement and heavy alcohol drinking. Initially, pharmacological studies indicated that opioid receptor antagonists, such as naloxone and naltrexone, decreased alcohol self-administration in animal models. Subsequent clinical trials demonstrated that the opioid antagonist naltrexone reduced alcohol drinking, alcohol craving, and relapse rates in detoxified, outpatient alcoholics. In fact, naltrexone was approved by the Food and Drug Administration as a pharmacotherapeutic agent for the treatment of alcohol dependence. Recently, several studies show that a genetic predisposition toward alcohol drinking is associated with increased responsiveness of the opioid system to alcohol. Current information linking the opioid system to the actions of alcohol have generated models speculating that alcoholics and their offspring have defective brain opioid activity resulting in abnormal reinforcement following ingestion of alcohol. To determine the validity of an opioid model for alcoholism, it would be necessary to generate accurate measurements of endogenous opioid tone in human subjects. One technique that can measure innate differences in endogenous opioid activity is the induction of opioid receptor blockade with an opioid receptor antagonist. To understand how blockade with an opioid receptor antagonist measures endogenous opioid activity, it is necessary to understand how modulation of cortisol is opioid-dependent. Following onset of stress, efferent fibers from several brain regions converge on the "initiator" of the hypothalamic-pituitary-adrenal (HPA) axis, namely the corticotropin-releasing factor (CRF) producing neurons of the hypothalamus. This input induces the glucocorticoid component of the stress response. The CRF-producing neurons receive this stress signal through several major neurotransmitter systems37: stimulatory input from serotonergic and noradrenergic innervation and inhibitory inputs from GABA- and -endorphin producing neurons. Once CRF is released into the hypophyseal-portal circulation, it stimulates ACTH secretion from the pituitary; ACTH then stimulates cortisol release from the adrenal gland. Naloxone, a non-selective opioid receptor antagonist, induces a rise in ACTH and cortisol by blocking the opioid component of the inhibitory activity directed at the CRF-producing neurons . As a result of opioidergic modulation of CRF neurons, the naloxone challenge test can identify inborn and acquired alterations in endogenous opioid activity. For example, persons with less opioid activity (less inhibitory tone directed at the CRF neuron) would be maximally blocked (plateau in cortisol) by a lower dose of naloxone compared to individuals with greater opioid activity (more inhibitory tone) who require higher doses of naloxone to induce blockade. Thus, opioid receptor blockade by naloxone provides a functional assessment of opioid activity.